The Strategic Plan (2005-2010) of the Pregnancy and Perinatology Branch of the NICHD includes the study of drugs used in pregnancy as a major component of their mission. The paucity of knowledge from drug and pharmacologic research in pregnancy has markedly disadvantaged the pregnant woman and her fetus. Our broad objective is to explore the novel concept that drug metabolism by the fetus is of focal importance in selection and use of therapeutic agents during pregnancy. One specific aim of our research is to apply this pharmacologic strategy to the use of anti-depression drugs in pregnancy with studies of the disposition of two selective serotonin reuptake inhibitors (SSRI) that have different metabolic profiles. The in vivo approach is to quantify and compare fetal metabolism of fluoxetine and sertraline, two SSRIs, in the pregnant baboon for correlation with in vitro measures of fetal and maternal metabolic enzyme activity. We anticipate results will yield information relevant to reducing the divergent risks for depressed pregnant women and those for her offspring. The goal is to minimize exposure of the fetus to the agents, whether active drug or metabolite, while at the same time providing effective therapy for the mother. A second specific aim investigates the hypothesis that the fetus exposure to SSRIs will have signs of excess serotonergic activity and will show signs of serotonergic withdrawal after discontinuation of drug. Clinical reports indicate that infants of pregnant women treated with SSRIs have a syndrome of serotonin excess or withdrawl after birth. The approach will be to measure changes in parameters of autonomic regulation of heart rate and variability, frequency and synchrony variables reflective of EEG activation and to relate these changes to concentration of active agent in the fetus. In these relatively acute (4-12 d) epochs of fetal exposure we expect to identify specific biomarkers of exposure and withdrawal from the drug and initial dose response profiles. This research is relevant to public health because maternal depression is a common psychiatric disorder (15 to 20%) and associated with multiple risks for both mother and baby when untreated. SSRI type drugs are very effective for depression; yet, under used for fear of risks to babies, such as withdrawal at birth or effects on brain development. Research will identify drugs that have the least impact on the fetus, reduced impact on post-natal development without restricting treatment of maternal depression. [unreadable] [unreadable] [unreadable]